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Communications Biology (2026)
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Diastolic dysfunction, defined by impaired relaxation and increased ventricular stiffness, is central to heart failure with preserved ejection fraction, yet cardiomyocyte-intrinsic mechanisms remain incompletely understood. Here, we show that SORBS2 is a vital component of murine cardiomyocyte adhesion complexes. Its genetic ablation in mice causes progressive diastolic dysfunction with preserved systolic function, accompanied by atrial enlargement and reduced survival. Postnatal cardiomyocyte-directed re-expression of SORBS2 restores diastolic indices and significantly improves longevity. Mechanistically, SORBS2 functions as an integrative scaffold linking adhesome integrity, cytoskeletal remodeling, and calcium homeostasis. SORBS2 deficiency increases microtubule detyrosination, reduces SERCA2 abundance, disrupts dyad-associated organization, which collectively impair active cardiomyocyte relaxation. Concurrently, this deficiency promotes extracellular matrix remodeling and myocardial fibrosis, driving passive ventricular stiffness. Pharmacological inhibition of microtubule detyrosination partially rescues relaxation defects. These findings establish SORBS2 as a key regulator of diastolic function and define a structural axis governing myocardial mechanics, offering potential therapeutic targets.
WTP was supported by NIH R01HL163937 and charitable donations to the Boston Children’s Hospital Department of Cardiology. F.L. was supported by an AHA postdoctoral fellowship.
Fujian Lu
Present address: Institutes of Biomedical Sciences, Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
Zexuan Wu, Camille Blandin, Jiehui Chen, Jiajin Li, Li He, Qing Ma, Anna Ponek, Dogacan Yucel, Fujian Lu & William T. Pu
Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, USA
Michael M. Peters & Kevin Kit Parker
Harvard Stem Cell Institute, Cambridge, MA, USA
William T. Pu
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Correspondence to Fujian Lu or William T. Pu.
The authors declare no competing interests.
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Wu, Z., Blandin, C., Chen, J. et al. SORBS2 regulates diastolic function through cytoskeletal networks and calcium handling. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10503-6
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DOI: https://doi.org/10.1038/s42003-026-10503-6
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Communications Biology (Commun Biol)
ISSN 2399-3642 (online)
© 2026 Springer Nature Limited
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